O-GlcNAc Modification of Proteins and Cancer Metastasis

Aberrant post-translation modifications, such as phosphorylation, of cellular proteins play a key role in cancer development and metastasis. A variety of nucleocytoplasmic proteins were found to be modified through a β-O-linkage of N-acetylglucosamine (GlcNAc) to serine or threonine residues, similarly to protein phosphorylation. However, (unlike phosphoryltaion,) only two enzymes catalyze the addition and the removal of O-GlcNAc: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. Aberrant patterns of O-GlcNAcylation on key proteins have been documented in pathological conditions such as diabetes neurodegenerative diseases and cancer. Therefore, we hypothesize that O-GlcNAcylation of nucleocytoplasmic proteins is altered during metastasis of human colorectal cancer and thus contributing to the transformation of tumor cells towards metastasis. The levels of O-GlcNAcylation and its enzymatic machinery in primary and metastatic colorectal cancer clones were followed. The expression of OGA was silenced by RNA interference, and the effect of this manipulation on gene expression, and cellular phenotype, was examined. Our results show that OGA level was found to be significantly lower in metastatic cells and in OGA-silenced cells, consistently with elevated O-GlcNAcylation level. OGA-silencing altered cell morphology and gene expression in a manner supporting our hypothesis.